This invention relates to a device and method for sampling of substances across tissue using electrical energy of alternating polarity.
Iontophoresis is employed for therapeutic topical treatment of humans or other organisms. Glikfeld et al., U.S. Pat. No. 5,279,543, describes the use of iontophoresis to non-invasively sample a substance through skin into a receptor chamber on the skin surface. The Glikfeld device consists of two chambers, each containing an electrically conductive medium, which medium is in electrical contact with the skin. A positive electrode (anode) is disposed in one chamber, and a negative electrode (cathode) is disposed in the other. The two chambers are separated by an electrically insulating material. In use, a constant or pulsed current is generated by a power source between the electrodes through the skin. The direction of current flow never changes during sampling. Glikfeld does not correlate the collected substance levels with blood substance levels and does not address any problems associated with long term transdermal monitoring of a substance.
The Lattin and Spevak U.S. Pat. No. 4,406,658, Tapper U.S. Pat. Nos. 4,301,794, 4,340,047 and 5,224,927, Masaki U.S. Pat. No. 4,786,278, Masaki U.S. Pat. No. 4,792,702 and Masaki European Patent No. 230,153 describe the iontophoretic delivery of a substance across tissue. In addition, these publications describe operation methods in which the polarity of the applied electrical energy is reversed during delivery. None of these publications addresses extraction of substances from tissue or any of the problems associated with such extraction.
The Tapper ""794 and ""047 patents address the irritation caused by iontophoretic delivery of ionized molecules through skin. In the Tapper apparatus, all delivery occurs at a single electrode. Tapper determined that the irritation can be eliminated if the polarity of the applied current is reversed for equal periods. A complete and equal polarity reversal eliminates the molecule delivery, however. Tapper compromises by providing for a shorter period for the reverse direction and a longer period for the forward (substance delivery) direction.
The Tapper ""927 patent discloses an apparatus that iontophoretically delivers a substance into the patient""s skin from two source reservoirs, each attached to an electrode. The electrodes are connected to an AC power source having a frequency in the range of 0.0027-10 Hz. Use of an AC power source minimizes the build-up of irritating chemicals at positive and negative electrodes (e.g., HCl and H2O2, respectively). Providing a source reservoir at both electrodes permits delivery from one of the reservoirs in each phase of the AC signal, thereby eliminating the drawback of using a single source reservoir noted in the earlier Tapper patents.
Some alternating polarity methods for drug delivery, such as in the Tapper ""927 patent focus on prevention of pH changes. For many electrode systems, water hydrolysis upon the application of current causes the pH to dramatically decrease at the anode and increase at the cathode. This can cause skin irritation. Furthermore, the pH changes in the drug donor electrodes can reduce the amount of ionized drug relative to non-ionized drug in the donor depending on the pKa of the drug. These patents propose switching between the anode and cathode to prevent these pH changes, reducing irritation and possibly increasing drug flux, especially of ionizable drugs.
The Lattin and Spevak ""658 patent allows for delivery from both electrodes, thus doubling the potential delivery area. For drug delivery applications, more area means more deliverable drug per application of a single device. However, for iontophoretic sampling applications, there is no advantage to doubling the area because total delivery is not an important factor. The amount that is sampled per area is more important because it is the substance concentration that is to be measured, not the total substance amount.
The Masaki patents disclose a device and a switch which can iontophorese both anions and cations by switching the polarity of the two electrodes during the treatment cycle. In the Masaki ""702 patent, the cations and anions come from a single source reservoir attached to one electrode. The other two patents do not disclose where the cation and anion sources are located. In any event, these patents teach nothing about iontophoretic sampling from skin into a reservoir.
Sibalis U.S. Pat. No. 5,013,293 describes an xe2x80x9celectrophoreticxe2x80x9d drug delivery system in which a drug is delivered from a reservoir into the patient""s skin under the action of current applied to two electrodes, one of which is attached to the reservoir. The polarity of the current may be alternated periodically to control the amount of drug delivered. Sibalis does not disclose the use of iontophoresis for removing a substance from a patient""s tissue.
LaPrade U.S. Pat. No. 5,006,108 discloses alternating polarity for the delivery of drugs in which the surface area of both electrodes (each alternating between being the anode and cathode) is available to deliver the drug. The LaPrade disclosure does not suggest that: (1) a single electrode may be used as a collector during iontophoretic extraction, with that electrode alternating between being an anode and a cathode; (2) two electrodes may act alternatively as anode and cathode during iontophoretic extraction, or (3) iontophoresis can be used generally for removing substances from tissue.
Some alternating polarity patents for drug delivery, such as the above LaPrade and Lattin patents, focus on increasing drug dosage with the same size patch. The principle is that the available surface area for delivery is larger for alternating polarity because each electrode can be both an anode and a cathode, rather than one electrode being the xe2x80x9cactivexe2x80x9d electrode and the other electrode taking up space, but not helping drug delivery, as the xe2x80x9cindifferentxe2x80x9d electrode. This results in more drug delivery, but would not aid in extraction where substance flux, not xe2x80x9ctotalxe2x80x9d substance delivered, is the critical factor.
Teijin LTD, Japanese patent publication 4224770, discloses an apparatus with electrodes for attachment to skin which has hydrous medium for electrically contacting the electrodes, containing medically active agent to be absorbed through the skin, and current polarity switching means. Apparently, this patent is designed to reduce pH deviation.
Teijin LTD, Japanese patent publication 3045272, discloses a compact iontophoresis device which comprises electrodes containing medicine and applied with high frequency AC for percutaneous administration and with the objective of reducing skin irritation.
In the area of in vivo extraction of substances from tissue, correlation between measured concentrations of extracted substances must be correlated with levels of the substance within the patient""s tissue and/or blood stream. For example, studies have shown a need for a virtual continuous glucose monitor, which could potentially signal a diabetic of dangerously low or high blood sugar levels. The greater the flux of the extracted substance from the tissue into the substance collector, the greater the accuracy with which the measured flux can be correlated with the concentration of the substance within the tissue and/or blood stream. What is needed, therefore, is a way to decrease the difference between the measured concentration of the extracted substance and the concentration of the substance within the tissue and/or blood.
Standard iontophoretic electrodes generally involve either water hydrolysis, which can cause undesirable pH changes, or a silver/silver chloride reaction in which silver chloride is converted to silver at the cathode, and silver is converted to silver chloride at the anode. For either of these systems, long term application of current can be a problem due to the eventual depletion of the reactants. What is needed, therefore, is a iontophoretic sampling system and method that avoids this problem.
This invention is directed to a device and method for sampling of a substance using electrical energy applied in alternating polarity. Alternating the polarity allows the reactions, such as silver/silver chloride reaction or the water hydrolysis reaction, to cycle back and forth, potentially lengthening the time that a particular electrode could be used. In the non-invasive sampling method of the invention the pertinent parameter is the extraction of the desired substance per unit surface area (flux), not the total extraction.
The invention includes a method for sampling of a substance from a subject, which comprises
(a) placing one or more sampling chambers on a collection site on a tissue surface of a subject;
(b) conducting electrical current through the tissue in a first polarity to extract a substance from the subject into one or more sampling chambers;
(c) reversing the polarity of the electrical current during the course of the method (i.e., changing an anode to a cathode and a cathode to an anode); and
(d) analyzing the sampling chamber or chambers for the concentration of the substance or a substance metabolite.
The invention also includes a sampling device comprising
(a) an electrical power supply means;
(b) a transdermal system that contains one or more sampling chambers for receiving a sample that function as both anode and cathode during the course of iontophoretic sampling;
(c) means for reversing the polarity of the power source during the iontophoretic sampling; and
(d) means for analyzing the sampling chamber or chambers for the concentration of the substance or a substance metabolite.
The invention also includes a substance monitor comprising:
first and second substance sampling chambers each containing substance collection medium selected from the group consisting of water, saline solutions, buffer solutions, and polyols;
a power supply means having a positive connector and a negative connector;
conductors and a switch electrically connecting the first and second sampling chambers to the power supply means positive connector and the power supply means negative connector, the switch having a first position in which the first sampling chamber is electrically connected to the positive connector and the second sampling chamber is electrically connected to the negative connector and a second position in which the second sampling chamber is electrically connected to the positive connector and the first sampling chamber is electrically connected to the negative connector.
The reversal of polarity during the sampling method of the invention has advantages over a prior standard iontophoresis method (non-alternating direct or intermittent current application) including: (1) there is unexpected enhancement of the correlation between blood and iontophoretically extracted samples under the alternating polarity method of the invention as compared to a non-alternating polarity protocol, (2) there is a particularly unexpected normalized flux rate increase over the use of direct current, and (3) the alternating polarity method of the invention enables continuous or intermittent application of current for Ag/AgCl or other electrodes without depletion of the AgCl plating or pH variations which occur for non-alternating systems.
The ionization state of the substance of the drug delivery materials of the prior art were dictated by the pH of the donor solutions. However, in the alternating polarity sampling method of the invention, the ionization state of the extracted substance does not rely on the pH of the donor chamber; rather, the ionization state of the extracted species going from the body to the top of the skin is dictated by the pH of the body, which is relatively constant.
The alternating polarity sampling method and device of the invention preferably uses low frequencies of about 0.1 Hz (one switch every 10 seconds) to about 1 switch every hour. This is in contrast to the drug delivery of the prior art, such as Tapper ""794 and Masaki ""351 which disclose that in a desire to reduce skin irritation, rapid, high frequency pulsing, of either the same or alternating polarity, reduces skin irritation caused by iontophoresis.
These advantages are surprising considering the non-invasive nature of the method and device which produces these advantages when transporting substances that are beneath the skin to a collection reservoir on top of the skin while no part of the device penetrates into or beneath the skin.